The Influence of Prenatal DHA Supplementation on Individual Domains of Behavioral Functioning in School-Aged Children: Follow-Up of a Randomized Controlled Trial

Docosahexaenoic acid (DHA) accumulates in the fetal brain during pregnancy and is thought to have a role in supporting neurodevelopment. We conducted a multicenter, double-blind, randomized controlled trial in women with a singleton pregnancy who were <21 weeks’ gestation at trial entry. Women were provided with 800 mg DHA/day or a placebo supplement from trial entry until birth. When children reached seven years of age, we invited parents to complete the Strengths and Difficulties Questionnaire (SDQ), the Behavior Rating Inventory of Executive Function (BRIEF), and the Conners 3rd Edition Attention-Deficit Hyperactivity Disorder (ADHD) Index to assess child behavior and behavioral manifestations of executive dysfunction. There were 543 parent–child pairs (85% of those eligible) that participated in the follow-up. Scores were worse in the DHA group than the placebo group for the BRIEF Global Executive, Behavioral Regulation and Metacognition Indexes, and the Shift, Inhibit, Monitor, Working Memory, and Organization of Materials scales, as well as for the Conners 3 ADHD index, and the SDQ Total Difficulties score, Hyperactivity/Inattention score, and Peer Relationship Problems score. In this healthy, largely term-born sample of children, prenatal DHA supplementation conferred no advantage to childhood behavior, and instead appeared to have an adverse effect on behavioral functioning, as assessed by standardized parental report scales.

Pushing or Pulling Your “Poison”: Clinical Correlates of Alcohol Approach and Avoidance Bias Among Inpatients Undergoing Alcohol Withdrawal Treatment

Introduction: Alcohol approach bias, the tendency to automatically move toward alcohol cues, has been observed in people who drink heavily. However, surprisingly, some alcohol-dependent patients demonstrate an alcohol avoidance bias. This inconsistency could be explained by the clinical or demographic profile of the population studied, yet this has not been examined in approach bias modification (ABM) trials to date. We aimed to determine the proportion of patients with an approach or avoidance bias, assess whether they differ on demographic and drinking measures, and to examine the clinical correlates of approach bias.Method: These research questions were addressed using baseline data from 268 alcohol-dependent patients undergoing inpatient withdrawal treatment who then went on to participate in a trial of ABM.Results: At trial entry (day 3 or 4 of inpatient withdrawal), 155 (57.8%) had an alcohol approach bias and 113 (42.2%) had an avoidance bias. These two groups did not differ on any demographic or relevant drinking measures. Approach bias was significantly and moderately associated with total standard drinks consumed in the past 30 days (r = 0.277, p = 0.001) but no other indices of alcohol consumption or problem severity.Conclusion: Whilst the majority of alcohol-dependent patients showed an alcohol approach bias, those with an avoidance bias did not differ in demographic or clinical characteristics, and the strength of approach bias related only to recent consumption. Further research is needed to develop more accurate and personally tailored measures of approach bias, as these findings likely reflect the poor reliability of standard approach bias measures.

Preliminary results from a phase II trial of docetaxel before castration with degarelix in men with newly diagnosed metastatic prostate cancer.

116 Background: Randomized trials have demonstrated a survival advantage to administering docetaxel (D) shortly after initiation of androgen deprivation therapy (ADT) in men with newly diagnosed hormone sensitive metastatic prostate cancer (hsMPC). Clinical trials in breast cancer, research in prostate cancer cell lines, and pharmacokinetic analyses of D clearance in the castrate state, suggest increased efficacy of chemotherapy administered separately from hormone suppression. We proposed that treatment with D before ADT might improve outcomes in newly diagnosed hsMPC. Methods: In an ongoing phase II study (NCT03069937), men with newly diagnosed hsMPC were treated with 4 cycles of D (75mg/m2) every 21 days without ADT followed by 2 cycles of D concurrent with the LHRH antagonist degarelix (Deg) administered every 4 weeks. The Deg alone was continued for a total of 7 injections. Men were trial eligible with high or low volume disease by CHAARTED criteria. Bicalutamide was allowed for < 30 days before trial entry, but LHRH directed therapy was not permitted. The primary endpoint for this trial is percentage of men obtaining PSA < 0.2 ng/ml. Pre-specified secondary endpoints examined here after 4 cycles of docetaxel alone are safety, and efficacy defined by PSA (decrease by > 50%) and radiographic responses. Results: At time of this abstract, 50 patients have been enrolled to trial. Two patients withdrew after 1 cycle of D, and 4 patients have not yet completed 4 cycles. Of the 50 patients evaluable for safety, 6 (12%) had Grade 3 toxicities related to D. No Grade 4/5 toxicities were reported. Of patients who completed 4 cycles of D, 24/44 (55%) had a PSA response and 34/44 (77%) had PSA decline from baseline. All but two patients with declining PSA had stable or improved radiographic imaging. Six of the 44 patients (14%) had PSA progression (>25% increase) with D therapy, 3 of whom also had radiographic progression. Every patient with PSA response after 4 cycles D had PSA decline after 2 cycles. No patient with PSA decline after 2 cycles had PSA progression after 4 cycles. PSA response rate was stratified by baseline variables in table below. Conclusions: In hsMPC patients, 4 cycles D without ADT appears to be a safe and active therapy. Treatment with bicalutamide prior to the start of D predicts poorer PSA response. This result strengthens our hypothesis that sensitivity of hsMPC to taxane therapy may be enhanced if ADT is postponed. Baseline genomics will be analyzed, and we hope to correlate responses to D alone with later primary efficacy outcomes. Clinical trial information: NCT03069937. [Table: see text]

Abstract 15140: Older Participant Perspectives on Permanent Study Drug Discontinuation in an Ongoing Primary Prevention Trial of Statins: A Qualitative Study

Introduction: Study drug discontinuation is commonplace in clinical trials of older populations and poses a major challenge to trial investigators. Little is known about why older participants discontinue the study drug. This study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥70 years within an ongoing primary prevention trial of statins by tapping into their experiences and perceptions. Methods: Trial participants who had permanently discontinued the study drug within 2 years of randomization were purposively sampled based on age (<75 and ≥75 years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analyzed thematically. Results: Thirty participants took part (21 females; mean age, 77 years) and three themes were identified from the data. Perceived adverse events (AEs) and their impact on daily living (mobility, functional capacity, quality of life, etc.) were identified as the major factors leading to the participants permanently discontinuing their study drug. Muscle symptoms were the most commonly reported AE. Selected participant quotes which describe symptoms and their impact are presented in Table. For some, a challenging life circumstance further lowered their tolerance to the perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. concerns about possible side effects, GP advice, unrelated illness). Conclusion: Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry and offering timely medical assistance and support when AEs occur may be useful to reduce drug discontinuation rates.

Impact of Etiological Cytogenetic Abnormalities on Immunoparesis and Progression-Free and Overall Survival in Newly Diagnosed Multiple Myeloma

Introduction: Immunoparesis, or suppression of polyclonal immunoglobulins, is a common issue in multiple myeloma (MM). Prior studies have shown that the degree of IgM immunoparesis is prognostic for survival, as patients with the most severe IgM immunoparesis at diagnosis have the poorest survival outcomes. Little is known regarding the cause of this immunoparesis, with many assuming it is due to tumor bulk alone. More recent data has suggested that MM can be divided into subgroups with distinct biologies and outcomes based on etiological cytogenetic abnormalities. These include hyperdiploidy and translocation t(11;14), t(4;14), t(14;16), or t(14;20), with the latter three groups being associated with high-risk disease. We hypothesized that the different etiological cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis and subgroup-dependent effects on clinical outcomes. Methods: We performed a retrospective review of newly diagnosed MM patients enrolled in the MRC Myeloma IX and Cancer Research UK Myeloma XI trials. Patients with hyperdiploidy, t(11;14), t(4;14), t(14;16), or t(14;20) were included in the analysis. Polyclonal IgG, IgA, and IgM levels were measured at diagnosis, and the normal range was established by the 5th - 95th percentiles of adults over age 45 years in the UK: IgG 6 - 16 g/L, IgA 0.8 - 4 g/L, and IgM 0.5 - 2 g/L. Cytogenetic abnormalities were determined by FISH, multiplex ligation-dependent probe amplification (MLPA), or next generation sequencing (NGS). Overall survival (OS) was defined as time from date of trial entry to date of death, or censored at date last known to be alive. Progression-free survival (PFS) was defined as time from date of trial entry to progression or death, or censored at date last known to be alive and progression-free. Results: The study included 985 patients, of whom 47% were at least age 65 years and 61.1% were male. The most common MM subtype was IgG (63.4%), followed by IgA (24.5%), light chain only (8.4%), IgD (1.9%), oligosecretory (1.0%), IgM (0.5%), and non-secretory (0.3%). Hyperdiploidy represented 58.9% of cases, with t(11;14) seen in 18.2%, and t(4;14), t(14;16), or t(14;20) seen in 22.9%. The MM subtype was not distributed evenly amongst the different etiological cytogenetic abnormalities with IgG overrepresented in the hyperdiploid subgroup (69.4%), compared to 11% in t(11;14) and 19.5% in high-risk cases. IgA was overrepresented in high-risk cases (45.2%), compared to 41.1% in hyperdiploidy and 13.7% in t(11;14). The high-risk subgroup had more immunoparesis compared to the hyperdiploid and t(11;14) subgroups (median polyclonal IgG 3.0 vs. 3.8 vs. 3.9 g/L, IgA 0.2 vs. 0.4 vs. 0.2 g/L, IgM 0.1 vs. 0.2 vs. 0.2 g/L, respectively). There were also significantly more patients in the high-risk subgroup with polyclonal immunoglobulin levels below the normal range compared to the hyperdiploid and t(11;14) subgroups (IgG 96.9% vs. 86.0% vs. 88.2%, p = 0.0045; IgA 89.9% vs. 77.1% vs. 92.4%, p &lt; 0.0001; IgM 94.0% vs. 88.9% vs. 92.7%, p &lt; 0.0001). With median follow up of 77 months, the overall median PFS and OS were 19 months and 53 months, respectively. As expected, patients in the high-risk subgroup had significantly lower PFS and OS (14 and 35 months, respectively, p &lt; 0.001), compared to the hyperdiploid (21 and 60 months) and t(11;14) subgroups (22 and 53 months). The effect of the degree of immunoparesis on PFS depended on the cytogenetic subgroup. Using polyclonal IgM as a continuous variable, Cox regression analysis demonstrated a significant effect on PFS in patients with hyperdiploidy (HR 0.482, 95% CI 0.325 - 0.717, p = 0.0003). No difference was seen in the t(11;14) (HR 0.610, 95% CI 0.262 - 1.418, p = 0.2507) or high-risk subgroups (HR 1.087, 95% CI 0.505 - 2.341, p = 0.8304). Conclusions: Our study demonstrates that the etiological cytogenetic subgroup influences the degree and clinical impact of immunoparesis in newly diagnosed MM patients. A significant proportion of patients with t(4;14), t(14;16), or t(14;20) have IgG, IgA, and IgM levels below the normal range compared to patients with hyperdiploidy and t(11;14). This suggests that the underlying genetic abnormality (i.e., NSD2, C-MAF, and MAF-B, respectively) drives changes in the bone marrow microenvironment remodeling the plasma cell niche, resulting in suppression of normal plasma cell function and immunoglobulin levels. Disclosures Cairns: Celgene: Other: Travel Support; Celgene, Amgen, Merck: Research Funding. Menzies:Celgene, Amgen, Merck: Research Funding. Pawlyn:Takeda: Consultancy, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses. Morgan:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Cook:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy. Kaiser:Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses. Jackson:Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Gsk: Honoraria, Speakers Bureau. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Histological Endpoints for Nonalcoholic Steatohepatitis Trials: Lights and Shadows

Nonalcoholic steatohepatitis (NASH) with liver fibrosis is an increasingly important cause of liver-related morbidity and mortality. A diagnosis of NASH can only be made using liver biopsy. Liver histology also forms the endpoint for the expedited licensing strategies that have been approved by regulators to allow patients with NASH access to treatment before the impact of these on clinical outcomes is known. Validation of these histological surrogate endpoints is critical for the ongoing development of new therapies for NASH. The use of liver biopsy to define both trial entry and endpoints raises questions about the use of treatments for NASH in practice when the effectiveness of treatment will likely depend, at least in part, on the use of histology for patient selection in the real world.

Radiofrequency denervation of the lumbar facet joints: guidelines for the RADICAL randomised controlled trial

Background and aim: The RADICAL trial has been funded by the National Institute for Health Research (NIHR) to evaluate the clinical and cost-effectiveness of radiofrequency denervation (RFD) for low back pain. Recommendations have been published which aim to standardise selection of patients and RFD technique. However, it is important to ensure these recommendations are acceptable to clinicians within the context of the trial. The aim of this work was to develop standardised criteria for the trial entry and RFD technique for implementation within the RADICAL trial. Methods: Fourteen pain clinicians completed a survey, which involved reviewing the current recommendations and indicating whether they disagreed with any of the recommendations and if so why. Responses were collated and presented at a half-day workshop with 14 attendees. During the workshop, the National Low Back and Radicular Pain Pathway (NLBRPP) guidelines for patient selection and an article by Eldabe and colleagues presenting recommendations on the RFD technique were reviewed. Attendees discussed whether each component of the recommendations should be mandatory, mandatory with alteration or clarification or optional within the RADICAL trial. Results: Attendees agreed during the workshop that 5 of the 10 criteria for patient selection described in the NLBRPP should be mandatory within the RADICAL trial. Three were agreed as mandatory criteria but required further clarification, one of which involved defining a positive response to a diagnostic medial branch block as ⩾60% pain relief. Two criteria had optional components. After reviewing the recommendations on the RFD technique from Eldabe and colleagues, seven components were agreed as mandatory, three were mandatory with alterations and three were optional. Conclusion: When evaluating complex interventions, such as RFD, it is important to ensure agreement and clarity on the clinical protocol, so that the intervention can be reproduced, if found to be effective.

Evaluation of DNA repair biology signatures to predict specific carboplatin (C) versus docetaxel (D) benefit in advanced triple-negative breast cancer (aTNBC).

1074 Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 & DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT & recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 & 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT & REC. CIN70 increased from PT to REC, DDRD (non-significantly) & PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 & DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]

Use of treatment pathways reduce cost and increase entry into clinical trials in patients (pts) with non-small cell lung cancer (NSCLC).

e21000 Background: VIA Oncology evidence-based pathways have been integrated into our medical oncology workflows since November 2014. Within 3 months, compliance was high for our 42 medical oncologists at 19 sites working with a common EHR with over 85% of pts treated on pathway. The aim of this study was to determine if there was a significant difference in the overall cost of treatment between pts treated on pathway versus off pathway, and whether on pathway pts had a lower rate of ED use and unplanned admissions within 30 days of chemotherapy as required in the new CMS directives. Methods: Newly diagnosed NSCLC pts diagnosed between January 1, 2017 to December 31, 2018 were identified from the tumor registry for the system. The VIA database was queried to separate these pts into two groups – those pts who were treated on pathway, and those who were off pathway. In addition, we divided pts into early diagnosis, advanced/curative, and advanced/non-curative. The data warehouse was utilized to determine the total charges of adjuvant medical oncology treatment for these pts. In addition, data was extracted for the same groups to determine those pts who sought ED evaluation and or hospital admission within 30 days of chemotherapy treatment (CMS-35). Statistical analysis was performed using Chi-square/Fisher’s exact test to compare proportions and t-test for independent samples to compare treatment costs and ED/hospitalizations between the on and off pathway groups. Results: During the 2 years, 407 (81.4%) NSCLC pts were treated on pathway (including clinical trials); 93 (18.6%) were off pathway. All patients undergoing treatment were ECOG 0-2 Performance Status. Mean cost for treating the on-pathway group was $104,436 compared to $183,717 for the off-pathway pts (p = 0.01). Since implementing pathways, clinical trial entry rose from 27 to 66/yr. 25.8% of on pathway compared to 29% of off pathway fell into the CMS 35 group. Conclusions: Standardized usage of evidence-based pathways can be used successfully across a large number of providers over wide geography. Adherence to pathways results in significant cost savings for each patient and significant rise in clinical trial entry.